Structure of a Gene Regulatory Network.
A gene regulatory network
or genetic regulatory
network (GRN)is a collection of DNA segments in a cell which interact with each other (indirectly through their RNA and protein expression products) and with other substances in the cell, thereby governing the rates at which genes in the network are transcribed into mRNA. In general, each mRNA molecule goes on to make a specific protein (or set of proteins). In some cases this protein will be structural, and will accumulate at the cell-wall or
within the cell to give it particular structural properties. In other cases the protein will be an enzyme; a micro-machine that catalyses a certain reaction, such as the breakdown of a food source or
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Control process of a Gene Regulatory Network.
toxin. Some proteins though serve only to activate other genes, and these are the transcription factors that are the main players in regulatory networks or cascades. By binding to the promoterregion at the start of other genes they turn them on, initiating the production of another protein, and so on. Some transcription factors are inhibitory.
In single-celled organisms regulatory networks respond to the external environment, optimising the cell at a given time for survival in this environment. Thus a yeast cell, finding itself in a sugar solution, will turn on genes to make enzymes that process the sugar to alcohol.[1] This process, which we associate with wine-making, is how the yeast cell makes
its living, gaining energy to multiply, which under normal circumstances would enhance its survival prospects.
In multicellular animals the same principle has been put in the service of gene cascades that control body-shape.[2] Each time a cell divides, two cells result which, although they contain the same genome in full, can differ in which genes are turned on and making proteins. Sometimes a 'self-sustaining feedback loop' ensures that a cell maintains its identity and passes it on. Less understood is the mechanism of epigenetics by which chromatin modification may provide cellular memory by blocking or allowing transcription. A major feature of multicellular animals is the use of morphogen gradients, which in effect provide a positioning system that tells a cell where in the body it is, and hence what sort of cell to become. A gene that is turned on in one cell may make a product that leaves the cell and diffuses through adjacent cells, entering them and turning on genes only when it is present above a certain threshold level. These cells are thus induced into a new fate, and may even generate other morphogens that signal back to the original cell. Over longer distances morphogens may use the active process of signal transduction. Such signalling controls embryogenesis, the building of a body plan from scratch through a series of sequential steps. They also control maintain adult bodies through feedback processes, and the loss of such feedback because of a mutation can be responsible for the cell proliferation that is seen in cancer. In parallel with this process of building structure, the gene cascade turns on genes that make structural proteins that give each cell the physical properties it needs.
Overview
At one level, biological cells can be thought of as "partially-mixed bags" of biological chemicals – in the discussion of gene regulatory networks, these chemicals are mostly the mRNAs and proteins that arise from gene expression. These mRNA and proteins interact with each other with various degrees of specificity. Some diffuse around the cell. Others are bound to cell membranes, interacting with molecules in the environment. Still others pass through cell membranes and mediate long range signals to other cells in a multi-cellular
Gene regulatory network 53 organism. These molecules and their interactions comprise a gene regulatory network. A typical gene regulatory network looks something like this:
The nodes of this network are proteins, their corresponding mRNAs, and protein/protein complexes. Nodes that are depicted as lying along vertical lines are associated with the cell/environment interfaces, while the others are free-floating and diffusible. Implied are genes, the DNA sequences which are transcribed into the mRNAs that translate into proteins. Edges between nodes represent individual molecular reactions, the protein/protein and protein/mRNA interactions through which the products of one gene affect those of another, though the lack of experimentally obtained information often implies that some reactions are not modeled at such a fine level of detail. These interactions can be inductive (the arrowheads), with an increase in the concentration of one leading to an increase in the other, or inhibitory (the filled circles), with an increase in one leading to a decrease in the other. A series of edges indicates a chain of such dependences, with cycles corresponding to feedback loops. The network structure is an abstraction of the system's chemical dynamics, describing the manifold ways in which one substance affects all the others to which it is connected. In practice, such GRNs are inferred from the biological literature on a given system and represent a distillation of the collective knowledge about a set of related biochemical reactions.
Genes can be viewed as nodes in the network, with input being proteins such as transcription factors, and outputs being the level of gene expression. The node itself can also be viewed as a function which can be obtained by combining basic functions upon the inputs (in the Boolean network described below these are Boolean functions, typically AND, OR, and NOT). These functions have been interpreted as performing a kind of information processing within the cell, which determines cellular behavior. The basic drivers within cells are concentrations of some proteins, which determine both spatial (location within the cell or tissue) and temporal (cell cycle or developmental stage) coordinates of the cell, as a kind of "cellular memory". The gene networks are only beginning to be understood, and it is a next step for biology to attempt to deduce the functions for each gene "node", to help understand the behavior of the system in increasing levels of complexity, from gene to signaling pathway, cell or tissue level (see systems biology).
Mathematical models of GRNs have been developed to capture the behavior of the system being modeled, and in some cases generate predictions corresponding with experimental observations. In some other cases, models have proven to make accurate novel predictions, which can be tested experimentally, thus suggesting new approaches to explore in an experiment that sometimes wouldn't be considered in the design of the protocol of an experimental laboratory. The most common modeling technique involves the use of coupled ordinary differential equations (ODEs). Several other promising modeling techniques have been used, including Boolean networks, Petri nets, Bayesian networks, graphical Gaussian models, Stochastic, and Process Calculi. Conversely, techniques have been proposed for generating models of GRNs that best explain a set of time seriesobservations.
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